Drug residue formation from ronidazole, a 5-nitroimidazole. II. Involvement of microsomal NADPH-cytochrome P-450 reductase in protein alkylation in vitro.
Purified liver microsomal NADPH-cytochrome P-450 reductase is able to catalyze the activation of [14C]ronidazole to metabolite(s) which bind covalently to protein. Like the reaction catalyzed by microsomes, protein alkylation catalyzed by the reductase is (1) sensitive to oxygen, (2) requires reducing equivalents, (3) is inhibited by sulfhydryl-containing compounds and (4) is stimulated several fold by either flavin mononucleotide (FMN) or methytlviologen. A cytochrome P-450 dependent pathway of ronidazole activation can be demonstrated as judged by the inhibition of the reaction by carbon monoxide, metyrapone and 2,4-dichloro-6-phenylphenoxyethylamine but the involvement of specific microsomal cytochrome P-450 isozymes has not been definitively established. Milk xanthine oxidase is also capable of catalyzing ronidazole activation. Polyacrylamide sodium dodecyl sulfate (SDS)-gel electrophoresis reveals that the reactive intermediate(s) of ronidazole does not alkylate proteins selectively.
D000478:Alkylation; D000693:Anaerobiosis; D000818:Animals; D005486:Flavin Mononucleotide / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D009593:Nitroimidazoles / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D012385:Ronidazole / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D009593:Nitroimidazoles; D012710:Serum Albumin, Bovine; D008748:Methylcholanthrene; D005486:Flavin Mononucleotide; D012385:Ronidazole; D014969:Xanthine Oxidase; D009251:NADPH-Ferrihemoprotein Reductase